Practical Aspects of Antibiotic

Selection
Debbie Tristram, MD
Professor of Pediatrics
Albany Medical College

Learning Objectives
Understand the role of antibiotics in
management of infection
Explain the rationale behind the drugs of choice
for a given infection
Review the guidelines for the use of antibiotics
(and when not to use them)

The most important question of

all with regard to antibiotics

Does the patient REALLY

need antibiotics?

The dark side of antibiotic use

ID has its own war on terrorism..(but we are not on the

side of the Resistance!)

Antibiotics are a double-edged sword: Effects on

normal flora

Friendly Fire
Innocent Bystander
Collateral Damage

Normal flora
Skin/muscosal surface: Staphylococcus,
Corynebacterium, Candida
Oral cavity: Streptococcus viridans, Streptococcus
pyogenes, Neisseria, Moraxella, Fusobacterium,
Bacteroides, Candida
GI tract: Lactobacillus, Enterococcus, E. coli,
Klebsiella, Bacteroides, Bifidobacteria, Candida,
Clostridium
GU tract: Corynebacterium, Lactobacillus,
Streptococcus, Mycoplasma, Candida,
Fusobacterium, Bacteroides

Scalp

10 5-7
10 9

10 5-7

Eyes

10 5-6
10 <1-3
102

1010
3-43-6

10
10 5

9-11

10 6

Normal
flora
during
health in
adults
Skin
below
the neck

10 6-7

Effects of Antibiotics on Intestinal

Flora in Normal Volunteers
Antibiotic

Ceftriaxone

Pip/tazo

Clindamycin

Enterobacteria

Anaerobic
bacteria

Candida

C. difficile

YOUR PATIENTS COLON ON

DRUGS!

The dark side of antibiotics

Antibiotics select for resistant organisms.
Antibiotics promote overgrowth of resistant
organisms in non-sterile sites (mouth, skin, GI tract,
GU tract).
Disruption of normal flora is responsible for
colonization AND infection with VRE, C. difficile,
Candida, MRSA, Stenotrophomonas and other
resistant gram negatives
Broad-spectrum antibiotic means it kills more
enteric flora and causes more diarrhea.
BE NICE TO YOUR PATIENTS COLON: DONT OVERUSE
ANTIBIOTICS!

Judicious use of antibiotics

Follow guidelines set out for judicious use of
antibiotics
Educate your patients and families about the
down side of inappropriate antibiotics
Ask yourself each time- does the patient really
need this? And if so, try to make the best and
most narrow choice possible

Judicious use of antibiotics (90-95 compared to

subsequent 5 years in ED, private practice and clinic settings)

Reduced scripts for bronchitis by 40%

Overall scripts for antibiotics decreased by 15-30%
Patient satisfaction, return visits and complication
rates have not climbed
More limited data suggesting that rate of
development of resistance is slowing
resistance in SPN decreased by 28% in Eskimo villages
(similar results in Iceland and Canada studies)

Pichichero et al 2000, Pediatrics; Gonzales et al 1999,JAMA; Finkelstein et al

2001,Pediatrics.

Practice Guidelines for Adult and Pediatric

outpatient management
AAP guidelines for pediatric acute OMuse of
SNAP (safety net antibiotic prescription) or wait and see
without antibiotic
Acute pharyngitisno antibiotics without
positive rapid streptococcal antigen
URI
Lower respiratory tract infection

Gwaltney,JAMA 1967;202:158

Do you still want to (or need to)

use antibiotics..?
If so, the right one is critically
important!

What are the most important

considerations in choosing an antibiotic?
The bug
The drug
The host

The local environment of infection

The bugs
CULTURE!
Dont hesitate, youll be glad
you did!

Choice of antibiotics
The bug
What is the susceptibility of the
organism? (particularly ones local
resistance patterns)
Where is the infection located?
What are the organisms growth
characteristics?

MIC: Minimum inhibitory concentration

the minimum concentration of antibiotic in an in
vitro system capable of inhibiting the growth of 105
organisms in broth or agar culture systems
concentrations chosen to reflect ranges of antibiotic
achievable in vivo-- Different classes of antibiotic
have different MICs
The smaller the number the better (in general)
because this is the lowest concentration that will
inhibit the bug

Susceptibility
testing

http://www.petermp.dk/antibiotika.htm

Clockwise from top left:

Kirby Bauer-disk
susceptibility
E test strips-provide
full range MIC testing
Microtiter platesprovide breakpoint
susceptibility

Use of MIC90
In general, for optimal killing would like 4 times the MIC in
the area of infection (for CNS 10x)
For example, if MIC is 1ug/ml of oxacillin for Staph aureus
osteomyelitis, need >4ug/ml of oxacillin in the bone tissue
after a 500 mg dose (in adults), 37ug/ml achieved at 1
hour and 7 ug/ml at 8 hr in serum; penetration to synovial
fluid and bone comparable at 4 hours to serum levelan
other way to look at it is 25% of serum dose penetrates
the boneso peak penetration is about 9ug/ml and
trough is about 1.75ug/ml
still > 4 times the MIC at peak penetration

Use of MIC in CNS infection

250
200

50mg/kg
75mg/kg

150
100
50
0
plasma

CSF

Ceftriaxone-3 hours after

administration average
peak levels in CSF about
5% of administered dose
(about 5ug/ml for 50
mg/kg and about 25ug for
100mg/kg)
Want to reach 10 times the
MIC in CNS infections, so
the higher dose is better
when the MIC is 1-2 (to
achieve>20)

Most infections are extracellular

and are contained within the
interstitium
Serum levels of antibiotics
equilibrate rapidly with the
interstitium (in general) but there
are always exceptions

Exceptions to the rules: Situations where

interstitial fluid and serum do not reach
equilibrium
CNS, retina, prostate
these areas have non-fenestrated capillary beds
and diffusion is not as readily achieved for
molecules greater than 1000 D size
must rely on other mechanisms
active transport
pH partition
cellular reservoir

Exceptions to the rules: Intracellular

pathogens

Listeria
Salmonella
Brucella
Legionella
Mycobacterium
Rickettsia
Toxoplasmosis
Persistent (chronic) Staphylococcus and E.coli

Intracellular pathogens require

antibiotics that can penetrate the
host cell that harbors the bacteria
and still be effective

Intra- and Extracellular

antibiotics

Extracellular
Penicillins
cephalosporins
aminoglycosides

Intracellular
clindamycin
macrolides
quinolones

Growth characteristics of pathogens

Rapid versus slow- need bacteriocidal versus
bacteriostatic drugs
Early infection-rapid growth of bacteriacell
wall inhibitors are excellent
Later infection-bacteria start to reach steady
state and need alternative methods of
killing/inhibition

Susceptibility (or lack of it)

MRSA, MRSE
Depending on site may need Vancomycin, clindamycin, Bactrim or
Linezolid
VRE
Difficult to treat
May need Synercid, linezolid
ESBLs (extended spectrum beta lactamase producers)
Often multiply resistant to beta lactams, aminoglycosides
Need broad spectrum penicillin class drug with beta lactamase
inhibitor combo or quinolones
Incidence of ESBLs at PCMH has declined since Fortaz (ceftazidime)
was removed from the formularyauto substitution of Cefepime
Pen R Spn-choice of antibiotics depends upon the site of infectioneven
relatively resistant Spn can be treated by beta lactams if the infection
is not sequestered

The drug
Which one to use (or
2 or 3??)

CULTURE!
You know you want to..

Choice of antibiotics
The drug
Is it bacteriostatic or bacteriocidal?
Active metabolites?
*Can it provide high enough levels in the infected
area?
*Is the bug sensitive to it (or if empiric therapy,
does it cover most local bugs expected to be in
that type of infection?)

Bacteriostatic or bacteriocidal- does it really

matter?
Bacteriocidal
Beta lactams
Glycopeptides
(Vancomycin and
Teicoplanin)
Aminoglycosides
Metronidazole
TMP-SXT
Quinolones
(Rapid killing, in general)

Bacteriostatic

Bactrim
Oxazolidinones (Linezolid)
Streptogramins
Tetracyclines
Rifampin/Chloramphenicol/Ma
crolides (but can be cidal at higher
concentrations)

Dapsone
Nitrofurodantoin
(Maintain the status quo and let the
host clean up, in general)

Pharmacokinetic considerations in antibiotic

choice

Bound vs free drug

mode of administration
peak/trough vs AUC (area under curve)
reservoir in host cells
Side effects

Bound vs free drug

Most drugs bind to proteins, either albumin or
alpha-1 acid glycoprotein (AAG)
Drugs prefer to be free, in this form they travel
throughout the body, in and out of tissues and have their
biological effect

more highly bound drugs have a longer duration of

action and a lower volume of distribution
If a drug is highly protein bound, you need to give more to
get a therapeutic effect since so much is stuck to protein

Mode of administration
Enteral vs parenteral
Usually common sense to give IV/IM when GI
tract not functioning normally
IV to PO when patient improved and can tolerate
PO (assuming that there is a PO drug (and for
kids that they will take it!)

Synergy
Usually used in situations where the primary drug is
bacteriocidal but its effect will slow when the
organisms are no longer rapidly growing OR where
one wants to sterilize the site of infection as rapidly
as possible
Ampicillin or penicillin for GBS sepsis and meningitis,
certain gram negative infections nearly always need dual
coverage (pseudomonas family)
Endocarditis

Synergy versus Antagonism

Bacterial growth in log#

control

Drug A+Bantagonism

Drug A
Drug B
Drug A+Bsynergy

Time in hours

2 (or more?) antibiotics

Primarily used where antibiotic penetration is
erratic or there is lack of appropriate response
S. pneumoniae meningitis resistant to penicillin and
intermediate to ceftriaxone
Persistent SA /enterococcal bacteremia
Persistent positive CSF in shunt infections
TB (until the full susceptibilities are known for the
organism)situation where the development of
resistance is potentially highneed 2 drugs so use 4
initially)

Synergy and antagonism are not restricted

to antibiotics alone, many drugs can speed
or slow the metabolism of medications
have pharmacy help if patient on other
medications and you are not sure of the
interactions
(or use a computer based program such as
Lexicomp to assess interactions)

The local environment of infection

Local environmental factors influencing

antimicrobial activity
Acidic conditions (Abscess)
decreased activity of macrolides,
aminoglycosides and quinolones

Anaerobic conditions
Aminoglycosides and penicillins function poorly

growth rate of organisms

slow growth rate particularly affects drugs that
rely on inhibition of cell wall

The host

CULTURE!
You know you need to.

Choice of antibiotics
The host
Normal or immunocompromised?
Allergies?
Location of infection?
Expected organisms for body site or
disease? (for empiric therapy)

General uses for various antibiotics

Gram positives- pen/cephalos; clinda; vanco;
macrolides
Gram negatives-extended spectrum pcn and
cephalos; aminoglycosides; quinolones
Anaerobes- metronidazole; clinda; pcn class
drugs
Atypicals- macrolides, quinolones (in older
children and adults)

Factors contributing to antibiotic failure

Host-related
Foreign body present
Anatomic defect
Defect in host immune response to infection

Disease-related
Wrong antibiotic
Sequestered focus of infection
Non-bacterial infection or non-infectious

Antibiotic failures (cont)

Organism-related (* these are less commonly the problem)
Acquired resistance
Superinfection with resistant organism

Drug-related (host related)

Inadequate compliance
Improper dosing regimen
Inadequate diffusion into site
Drug-drug interactions
Deterioration of drug on storage

Antibiotics- Summary
CULTURE!!it will help if the patient does not respond to

know what you were dealing with initially

Know the resident or suspected organisms in the site of
infection
Know your local antibiotic resistance patterns
Know your host
Know the basics of changing antibiotics based on the
susceptibilities of the organism
Know the basics about the development of drug resistancealways use abx wisely and educate your patients and
families about the use and abuse of antibiotics

Quick References for the right bug for clinical

situation (empiric) and right bug/drug
combination for an isolate
Sanford Guide-updated yearly
Nelsons Pocketbook of Pediatric Infectious Diseaseupdated biannually
Albany Medical Centers antibiotic website-updated
yearly (under clinical, then tools)
The Red Book-updated every 2 or 3 years (most of
the time)
http://www.cdc.gov/getsmart/
for information on judicious antibiotic usage and
flyers for education of patients